Background: Factors that distinguish depressed individuals who become hopeless from those who do not are poorly understood. Method: In this study, predictors of hopelessness were examined in a sample of 439 clinically depressed adolescents participating in the Treatment for Adolescents with Depression Study (TADS). The total score of the Beck Hopelessness Scale (BHS) was used to assess hopelessness at baseline. Multiple regression and logistic regression analyses were conducted to evaluate the extent to which variables were associated with hopelessness and determine which cluster of measures best predicted clinically significantly hopelessness. Results: Hopelessness was associated with greater depression severity, poor social problem-solving, cognitive distortions, and family conflict. View of self, view of the world, internal attributional style, need for social approval, positive problem-solving orientation, and family problems consistently emerged as the best predictors of hopelessness in depressed youth. Conclusions: Cognitive and familial factors predict those depressed youth who have high levels of hopelessness.